The goals of this research are to develop advanced magnetic resonance spectroscopy (MRS) and imaging techniques and to apply them and other complementary methods to studying brain metabolism, neurotransmission and enzyme activity. MRS allows measurement of neurotransmission of glutamate and GABA in vivo, which play important roles in many major psychiatric diseases including depression and schizophrenia. During 2008-2009, significant progress was made in the development and applications of novel spectroscopic techniques for studying metabolism and neurotransmission in vivo in the brain. From our previous work with Dr. Gregor Hasler et al, we found that GABA concentration is decreased in patients with major depressive disorder but normal in remitted patients (Hasler et al, Biological Psychiatry, 58:969-973, 2005 and Archives of General Psychiatry, 64:193-200, 2007). Major depression has been considered to involve glutamate hyperactivity. Therefore, the GABA study sugests a link between GABA level and glutamate hyperactivity. We hypothesized that GABA level is negatively correlated with glutamate-glutamine cycling flux, the latter is an indicator of glutamtae efflux and measurable using MRS. To test this hypothesis, we conducted animal studies using proton MRS to measure GABA level and carbon-13 MRS to measure the glutamate-glutamine cycling flux. We used vigabatrin to elevate brain endogenous GABA. Vigabatrin is an anticonvulsant drug which specifically blocks GABA degradation. We found that the carbon-13 label flow from astroglial glutamine to neuronal glutamate is significantly reduced with increased GABA (Yang et al, J. Neural Transm., 116:291-300 (2009)). This result suggests a glutamatergic mechanism of GABA elevating drug, probably via GABAA-mediated inhibition of cortical glutamatergic neurons through interneurons. This result also sheds light on the mood-stablizing effect of GABAergic drugs. In addition, we have also extended our previously discovered carbon-13 magnetization transfer effect to studying the exchange between cytosolic and mitochondrial pools. By saturating the spins of mitochondrial fumarate we detected a saturation transfer effect on cytosolic aspartate. Our results provide direct evidence for the existence of fast exchanges of tricarboxylic acid (TCA) cycle intermediates and amino acids between mitochondria and cytosol (Yang et al, J. Cereb. Blood Flow Metab., 29:661-669 (2009)).